Chronic Alcohol Alteration of Influenza-Specific CD8 T cell Immunity and Protection

慢性酒精改变流感特异性 CD8 T 细胞免疫和保护

• 批准号: 9269492
• 负责人: Kevin L Legge
• 金额: $ 18万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-05 至 2018-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9269492
• 关键词: Alcohol abuse; Alcoholism; Alcohols; Bacterial Infections; Bacterial Pneumonia; CD8-Positive T-Lymphocytes; Cellular Immunity; Chronic; Consumption; Cytolysis; Defect; Dendritic Cells; Disease; Environment; Epidemic; Ethanol; Goals; Health; Heavy Drinking; Human; Immune response; Immunity; Immunosuppression; Immunosuppressive Agents; Incidence; Individual; Infection; Influenza; Influenza A Virus, H5N1 Subtype; Influenza A virus; Ingestion; Intestinal Mucosa; Intravenous; Intrinsic factor; Iowa; Knowledge; Lead; Lesion; Liver; Lung; Lung diseases; Mediating; Memory; Methodology; Modeling; Morbidity - disease rate; Mus; Mycoses; Nature; Outcome; Patients; Play; Pneumonia; Predisposition; Research Personnel; Respiratory Mucosa; Respiratory Tract Infections; Risk Factors; Role; Severities; Severity of illness; Skin; Spleen; T cell response; T memory cell; T-Lymphocyte; Universities; Virus Diseases; adaptive immune response; adaptive immunity; base; chronic alcohol ingestion; cooking; expectation; influenzavirus; intraperitoneal; mortality; mouse model; non-alcoholic; novel strategies; pandemic influenza; pathogen; problem drinker; public health relevance; respiratory; respiratory infection virus; response; subcutaneous

 DESCRIPTION (provided by applicant): Chronic alcoholism increases the incidence and severity of respiratory diseases and infections. Indeed, alcoholics compared to non-alcoholic individuals have increased mortality and morbidity during bacterial pneumonias. While much is known about the role that chronic alcohol plays in increasing the severity of respiratory bacterial infections, much less is understood about how chronic ethanol (EtOH) consumption alters the severity of pulmonary virus infections. Interestingly, our studies indicate that chronic consumption of EtOH increases both influenza virus associated morbidity and mortality. Further, our results demonstrate that this increased severity of disease is related to defects or alteration in influenza-specific CD8 T cell responses as well as respiratory dendritic cells (rDC). Importantly our findings of severe disease and poor outcomes using the Meadows-Cook model of EtOH consumption have been supported by a recent study in humans which showed that heavy alcohol use is a risk factor for severe outcomes during influenza virus infections. Therefore given the current threat of both epidemic and potential pandemic influenza a better understanding of the lesions within the pulmonary adaptive immune response in chronic alcoholics could lead to methodologies to boost immunity to this important human pathogen in these individuals. Our long- range goal is to determine what lesions chronic EtOH induces within the respiratory adaptive immune response. Within this application we will continue to use the Meadow-Cook chronic EtOH model as well as our mouse models of influenza virus infection to determine the contributions of the EtOH induced environment vs. T cell intrinsic lesions in the reduced CD8 T cell immunity during primary influenza virus infections of the chronic EtOH lung. Further as the CD8 T cell response in non immunologically naive individuals is made up of both new naïve T cell responses as well as existing T cell memory, this application will be the first t determine how chronic EtOH alters CD8 T cell memory that has been established prior to chronic EtOH consumption. Our central hypothesis is that the chronic EtOH induced lesion in the primary CD8 T cell response is made up of both environmental and T cell intrinsic defects and that chronic EtOH will reduce existing CD8 T cell memory. We propose the following Specific Aims: 1) Determine the contribution of "environmental" vs. T cell intrinsic factors to the EtOH induced lesion in the primary IAV-specific CD8 T cell response, 2) Determine how chronic ethanol consumption alters existing influenza-specific CD8 T cell memory and heterosubtypic protection against influenza virus infections. This application will not only define the defects tht chronic EtOH creates in pulmonary adaptive immunity during respiratory virus infections but should also increase our understanding of immunity during other (bacterial/fungal) respiratory infections.

 描述（由申请人提供）：慢性酒精中毒会增加呼吸道疾病和感染的发病率和严重程度。事实上，与非酒精性个体相比，酒精性个体在细菌性肺炎期间的死亡率和发病率增加。虽然我们对慢性酒精在增加呼吸道细菌感染的严重性方面所起的作用了解很多， 尽管慢性酒精（EtOH）消耗对肺部病毒感染的严重性有影响，但对慢性酒精（EtOH）消耗如何改变肺部病毒感染的严重性了解得少得多。有趣的是，我们的研究表明，长期消费乙醇增加了流感病毒相关的发病率和死亡率。此外，我们的研究结果表明，这种疾病严重程度的增加与流感特异性CD 8 T细胞应答以及呼吸道树突状细胞（rDC）的缺陷或改变有关。重要的是，我们使用Meadows-Cook EtOH消耗模型发现的严重疾病和不良结局得到了最近一项人类研究的支持，该研究表明，大量饮酒是流感病毒感染期间严重结局的风险因素。因此，考虑到目前流行性和潜在的大流行性流感的威胁，更好地了解慢性酒精中毒者肺部适应性免疫反应中的病变可能会导致提高这些个体对这种重要人类病原体的免疫力的方法。我们的长期目标是确定慢性乙醇在呼吸适应性免疫反应中诱导什么样的病变。在本申请中，我们将继续使用Meadow-Cook慢性EtOH模型以及我们的流感病毒感染小鼠模型，以确定慢性EtOH肺原发性流感病毒感染期间EtOH诱导的环境与T细胞内在病变对降低的CD 8 T细胞免疫力的贡献。此外，由于非免疫学幼稚个体中的CD 8 T细胞应答由新的幼稚T细胞应答以及现有的T细胞记忆组成，因此该应用将是第一个确定慢性EtOH如何改变在慢性EtOH消耗之前已经建立的CD 8 T细胞记忆的应用。我们的中心假设是，慢性EtOH诱导的病变的主要CD 8 T细胞反应是由环境和T细胞的内在缺陷和慢性EtOH将减少现有的CD 8 T细胞的记忆。我们提出了以下具体目标：1）确定“环境”与T细胞内在因素对免疫应答的贡献。 EtOH诱导的原发性IAV特异性CD 8 T细胞应答损伤。2）确定慢性乙醇消耗如何改变现有的流感特异性CD 8 T细胞记忆和针对流感病毒感染的异亚型保护。该应用不仅将定义慢性EtOH在呼吸道病毒感染期间在肺适应性免疫中产生的缺陷，而且还将增加我们对其他（细菌/真菌）呼吸道感染期间免疫的理解。